Targeting Cancers by Leveraging the Biology of Gamma Delta T Cells

Targeting Cancers by Leveraging the Biology of Gamma Delta T Cells

August 09, 2022PAO-07-022-CL-03

The cell therapy sector is expanding at a fantastic rate, particularly in oncology indications, but most of the efforts thus far have unsurprisingly focused on a subset of the full panoply of immune cell types. Building on the successes of chimeric antigen receptor (CAR) therapies using α/β T cells — and being mindful of their limitations — biopharma innovators have begun pursuing other immune cells, notably including γδ T (GDT) cells, which have inherent anti-cancer and antiviral properties and are free of some of the restrictions that have limited the creation of off-the-shelf allogeneic therapeutics. One company leading the way toward safer and less expensive CAR-T products targeting cancers is TC Biopharm. In this Q&A, Chief Executive Officer Bryan Kobel discusses the tremendous potential of GDT cells and the approach TC Biopharm is taking to their development with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D.

David Alvaro (DA): To get us started, how would you characterize the present moment in time for the whole development cycle of cell therapies?

Bryan Kobel (BK): This is an extremely exciting moment in the history of cell therapy. The first iterations of cell therapy were explorations for wound care way back in the 1990s. Following that, we saw the CAR-T movement around α/β T cells a decade ago — an early patient, Emily Whitehead, recently celebrated her 10-year anniversary of being cancer free following CAR-T treatment for acute lymphoblastic leukemia. Those were the first real proofs of concept of successful cell therapies in oncology. You can think about this progress along the lines of how technology advances in general: the first cell phone I had in the 1990s was huge and looked like a brick, and it could essentially only make phone calls and send and receive texts. But only 10 years later, things accelerated to the point where we had the iPhone, which is basically a minicomputer in your hand that allows you to do video calls and so much more. Technology tends to advance slowly at first and then accelerate more and more, sort of how Ernest Hemingway described going broke: very slowly at first and then very rapidly toward the end.

We’re now in that rapid acceleration phase for cell therapies. CAR-T therapies have produced some really wonderful results, and from there the cell therapy movement has really taken on a life of its own. Today, we have a significant number of cell therapies in the clinic and a range of advances going forward. Just looking at GDT cells, besides TC Biopharm, a number of companies — In8Bio, Adicet Bio, GammaDelta Therapeutics — are currently in the clinic. Then, if you include everything in the α/β space, the CAR technologies that Autolus and Algene are working on, and all the efforts with macrophages today, there’s an unbelievable amount of focus in the cell therapy sector right now, just in an indication basis. I think some of this reflects a more general focus in healthcare to use what our systems already do and use nature to make ourselves healthier rather than the blunt force, overengineered solutions of chemotherapy or whole-body radiation, where you’re hoping that a poison will kill unhealthy cells more than healthy ones. You see a similar phenomenon occurring around biohacking and things of that nature — just an overall desire in humanity to leverage our own biology to be healthier every day.

DA: I think that the concept of using α/β cells has really penetrated, but there is less understanding of the potential of GDT cells. Can you give us a quick primer on what’s unique about these cells and the therapeutic promise they present?

BK: Part of what’s so exciting about GDT cells is that we continue to learn new things about them every single day. But the easiest was to conceptualize GDT cells is that they’re the body’s first line of defense — basically the bouncers for the immune system. They float around in your system looking for the presence of an antigen called isopentenyl pyrophosphate (IPP), which is expressed by all sick and diseased cells — all tumors and all virally infected cells that have ever been discovered and studied — but not by healthy cells. So, GDT cells act like immunological sharks, floating around your system looking for this antigen, moving along concentration gradients to find the source of the IPP. When it finds the cells that are producing IPP, it triggers apoptosis and kills that cell.

As you get older and your cells continue to regenerate and proliferate, you’re always at some risk of accumulating mutations and creating cancers. One of the primary reasons why we don’t get cancer on a much more regular basis is these GDT cells locating and killing early cancer cells. Incidentally, they are also the reason why you don’t get the flu or any number of other viral diseases that you are constantly exposed to every single day: cells that are infected are killed before they have a chance to advance into an acute disease state. When cancer does take root, it typically means that it’s able to proliferate more quickly than this immune response, or that by the time the alarm bells start ringing, the cancer is already too advanced to be overwhelmed by the GDT system, either because the patient is immune suppressed or it’s simply an extremely aggressive cancer.

The therapeutic exploration of GDT cells arises from the question: what if we isolate activated GDT cells from somebody who’s really healthy, expand them into the billions, and administer them into a patient with an overwhelmed immune system? Can we turn the tide of that war with these activated GDT cells that we know can natively track down and kill these sick and diseased cells already on a naturalized basis? So far, we’ve seen success for that approach in relapsed/ refractory acute myeloid leukemia (AML), and we’re now moving it into second line for AML.

DA: With all of that potential, is there any particular reason why GDT cells haven’t been as widely explored to date? Has the issue been a knowledge issue or technology gap, or is it just contingent?

BK: It’s never just one thing! As you can imagine, we’re learning more and more about the body every single day, which is ultimately a function of overall technology: diagnostic tech like MRI machines, CAT scan machines, and so on, which are still evolving. But the primary reason why GDT cells haven’t been at the forefront of cell therapy before is simply that α/β cells are easier to find and to grow, so more groups focused on the cell type that was easier to work with; technology typically seeks the path of least resistance.

As α/β cells moved forward and as cell therapy started gaining momentum, Adrian Hayday, who is a founder at GammaDelta Therapeutics, wrote a great article that shone a new spotlight on GDT cells. As the understanding of the role of GDT cells in the immune system and the underlying mechanism has grown, they have become more of an area of focus for cell therapy developers, along with some other emerging modalities like macrophages, natural killer cells, mitochondrial factors, and so on. This will likely continue as more cell types are discovered and understood and eventually find their way into therapeutic applications.

DA: How important is the lack of MHC (major histocompatibility complex)/HLA (human leukocyte antigen) restriction in enabling allogeneic rather than autologous therapy to the pragmatic, economic promise of these cells?

BK: As much as we want to focus on the biology, at the end of the day, you have to consider the economics. It remains quite difficult to envision a broad economic use case for autologous therapies that require a unique, personalized therapeutic that’s based on each individual. There’s certainly value in autologous approaches in certain indications, but, broadly speaking, it’s a very difficult economic model.

We believe that the market is going to embrace allogeneic therapies. With GDT cells, there is no MHC restriction, and they don’t cause graft versus host disease (GVHD), which allows us to go outside of the HLA matching process that is used for bone marrow transplants. For bone marrow, matching the HLA genotype of the donor and the patient is really important, so the best hope is a first-degree relative, and the search can be very difficult otherwise. With no MHC restriction and hence no risk of GVHD, not only do you not need to derive the therapeutic from the patient, but you also open things up to a much larger population of donors.

However, even the donor process for cell therapies will have some restrictions, because there are only so many donors. As cell therapy grows, demand for those donors will grow. At some point, we will likely need to move into things like induced pluripotent stem cells (iPSCs), where you can derive an essentially unlimited amount of cells from that platform without needing additional donors. So, while allogeneic GDT cell therapies represent the next step in this trajectory, the subsequent one will involve IPSCs. There are some great companies working on that: BlueRock Therapeutics, Notch Therapeutics, and many, many others, all doing great work in that space among many other companies.

DA: As I understand it, on top of the natural anti-cancer activity of GDT cells, you’re also working on layering on co-stimulatory CAR receptor technology. Can you tell me a little bit about the idea behind that approach?

BK: One issue that we hear about a lot with CAR-T therapies, and the reason why patients can end up in the ICU, is the idea of on-site, off-tumor toxicity. Taking as an example a therapy that uses CD19 as the CAR receptor, the CAR-T α/β cell will target CD19 on tumor cells, but since CD19 is also found on healthy cells, the α/β cells can kill healthy cells as well. This is also why CAR-T cells aren’t effective against solid tumors: you can’t administer a sufficiently large dose to get the CAR-T cells out of the vasculature and into the tissue without a high rate of off-tumor effects.

Our co-stimulatory approach uses GDT receptor targeting IPP as an on/off switch for the CAR program. So, for example, if we are targeting the B7-H3 receptor — a potential target for solid tumors — with GDT CAR cells, the CAR cells will still attach to healthy cells, but since IPP isn’t present, it doesn’t complete the circuit needed to trigger apoptosis, and the CAR cell will detach without toxicity. However, if it finds a cancer cell expressing B7-H3, it will attach and complete the circuit for the kill signal. It’s basically magic. The guys who created this, our employees, are magicians doing amazing things every single day.

DA: Once you have this platform established, what are the considerations that enter into decisions about what indications to pursue, for both the unmodified GDT therapies and the CAR cell approaches?

BK: The allogeneic, unmodified gamma delta are ultimately the backbone of everything we do, but we had to determine where they were likely to be most efficacious. For us, this came down to the idea of combination therapy. You do hear a lot of companies say that they are pursuing monotherapies, but from our perspective, there may never be such a silver bullet, a monotherapy for cancer.

We looked at where we could be really helpful in combination basis with things like checkpoint inhibitors or bispecific antibodies or approaches to stimulate the immune system research around trying to turn cold tumors hot. By infusing activated GDT cells into a weakened immune system, we think we can enhance the effects of those therapies. I think that’s the strongest path forward for the allogeneic GDT cells, at least for solid tumors. We have had lots of discussions with any number of companies to develop opportunities for therapeutic combinations.

For the co-stimulatory approach, we also look for the indications where we can provide the most value, which may be an indication for which there is no treatment or where treatments options are very poor for the patient population: low life expectancy, few options, low quality of life — indications like pancreatic, ovarian, colorectal, breast, and non-small cell lung cancer and neuroblastomas. That’s where we really think that CAR and the combination therapies can be really impactful.

Beyond that, we are also exploring pediatric indications, because the unmodified GDT cells don’t have any toxicity. We should be able to dose pediatric patients in a number of different indications and be really, really impactful with very, very low toxicity for these patients. We talk regularly with groups that are focused on pediatric oncology to try and see what we can do there.

On the CAR side, we’re looking at indications around B7-H3 variants, as well as some brain indications, where there’s quite a lot to be done. We try to combine the economic benefit to drive shareholder value, which is obviously always at the forefront of our mind, with considering what will have the most value for patients and humanity more broadly.

DA: Can you share a bit about your individual clinical programs, what they are targeting, and the clinical progress you’ve made thus far?

BK: For our OmnImmune® program using the unmodified allogeneic GDT cells, which has orphan drug status in the United States, we have completed a phase I/II trial in relapsed/refractory AML. These are patients in palliative care with typically four to six weeks to live. We generated stellar data from that program. We have now launched a phase IIb/III trial in the UK and the EU, with three open sites in which we will hopefully being dosing in the next 60 days or so for our first cohort of 19 patients. We hope to be able to begin to announce data from that trial in the first half of 2023, and we’re really excited to see where that goes. This is a second-line product; after a patient fails in the first-line induction, they’ll receive our product as a bridge to transplant. We’ll also be transitioning that trial into the United States, and we’re hoping to have our FDA side of that trial prepared in Q4 of 2022. This will be really interesting from an investor perspective, because we should be able to see data out of the UK/EU in AML before or right after we start our U.S. trial, which means we’ll get AML as an indication.

From there, we will look at a number of different areas in which we can get our combination therapies into the clinic. We hope to have a combination therapy targeting solid tumors in the clinic in the first half of 2023, but we don’t yet know who our partner will be or which specific indication we will end up pursuing. Beyond that, we’re exploring how to advance our CAR program into the clinic in 2023, and it currently looks like that will target B7-H3, but we’re still doing some heavy work on that. We also have another preclinical cell program that we’re really excited about, which would be a combination therapy that we would do in-house, and we hope to get that into the clinic in 2023 as well. We are still trying to decide on our next steps, but our development team — including our co-founders COO Angela Scott and Executive Chairman Dr. Michael Leek — is doing a great job working on that.

DA: I understand that TC Biopharm is taking a somewhat atypical approach to both manufacturing and clinical research, keeping things in-house as much as possible. Can you tell me a little bit about that and why it makes sense to perform those activities yourselves?

BK: For cell therapies, it’s always hard to get a manufacturing perspective. If you’re going to be working with these cells every day, you need to understand them as best you can, which means you can’t just order cells from someone else and expect to understand them without really knowing how to make the cells. We decided that we needed to do that work in-house, so one of the first things we did is build the manufacturing plant.

On top of that, there is a real the supply–demand issue — there’s a real constraint in cell therapies today around access to cells from manufacturers. That’s why you see cell and gene therapy manufacturing plants going up all over the world. Our ability to move swiftly and our deep understanding of these cells is largely a function of our ability to manufacture them. A joke I often make is that, since we’re really at the forefront of knowledge on GDT cells, we are deep in the GDT jungle, swinging a machete every single day and ultimately either stepping on a pit of snakes or a pile of gold bricks.

Keeping those operations in-house has allowed us to morph ourselves into other areas with which we might otherwise have struggled. A good example is frozen-thawed product: we now have Omnimmune in a frozen-thawed basis, where we can freeze and ship the product and store it for up to nine months across the world, which means it is truly an off-the-shelf product. If there is a patient who will need an infusion of allogeneic GDT cells six months down the road, we can have frozen product stored in advance and ready to use when needed. That’s a core component of a true off-the-shelf technology: being able to call up the cell therapy storage place and order GDT cells and have them delivered that day — and it was enabled by our keeping all those things inhouse.

At the same time, rats and mice don’t have a functional GDT system, so you need to engineer the response when you do that preclinical work. There’s nothing inherently wrong with that approach, but we prefer to work in an environment that is more likely to translate. So, what would be animal work ends up in human phase Ib/II studies that provide us with safety data right away while allowing us to observe how it operates in actual patients and understand more to allow us to tweak dosages or make decisions aboutlipid depletion.

Doing things this way unlocks economic benefits by accelerating clinical trials and making them cheaper while allowing us to better understand cells and the function of the system in the patient, which makes for a better therapeutic when we actually develop it. It also spurs the development of other products or different uses of our products that may not have been possible if we were ordering a third-party cell bank. Mike (Leek) likes to joke that cells are sort of like teenagers: on some days, they wake up and they’re cranky, and on other days they wake up ready to go. You’re dealing with an organism more so than you are a chemistry. Outsourcing makes a lot of sense when it involves a chemical recipe, but cell therapy manufacturing requires a deep understanding of the actual cell itself, how it grows, when it’s at a point where you can freeze it, or when it's at the point where you should use it. And I think that Angela’s (Scott) expertise in GMP cell manufacturing and Mike’s expertise has driven us far in that regard.

DA: Is there anything else you can share about the team at TC and the culture and mission that is driving all of this innovation?

BK: A company is only as good as its people, and we build our team on a really strong foundation. Mike and Angela have each been in cell therapy for about 40 years. Angela is the “mother god” — she’s actually known as that — and she grew the cells that became the first cloned animal. Mike was part of the team that discovered and named apoptosis.

They’ve also done a great job of building a team around them. Dr. Sebastian Wanless, our Senior Clinical Director, spent 20 years at BMS successfully running clinical trials on every single continent (except for Antarctica — it’s pretty hard to infuse a polar bear with a drug) and was the driving force behind the global clinical trials for retroviral AIDS treatments. Emilio Cosimo, our Product Development Manager, has done an incredible job over the last several years moving development forward in a number of areas and keeping focus not only on what we are doing today but what we will be doing 12, 24, 36, or 48 months down the road. I see my role as essentially a mouthpiece amplifying all the great things that all these other people are doing, and it makes my job easier that they are always able to answer my questions in plain, layman’s English so that I simply have to repeat it. Mike and Angela have done an incredible job of hiring the right people, training them, and putting them in the best position to succeed, allowing us to be really nimble and effective. We’re excited as a team to be moving forward on programs that will really help people, and that’s what drives us all.

We also have a fantastic board: Morris, who’s on the board of Viridian and Cogent; Eddie Niemczyk, who sits on the board of Bridges Investment Management and as the healthcare PM there; James Culverwells in the UK; and Dr. Mark Bonyhadi, who’s a senior advisor at Qiming and was head of R&D at Juno Therapeutics, which led some of the first cell therapy revolutions. Having them as a neural network has been really incredible.

DA: Can you tell us about the decision to take the company public and the impact that had on TC’s trajectory?

BK: The reality is: at some point you have to take the next step as a company. For us, that next step was expanding our balance sheet and getting our story out, which the IPO allowed us to do. You can only tell so much as a private company, and we felt like it was time to access the capital markets and have currency with which to be nimble, whether that means making acquisitions, rewarding our investors and employees, bolting on a new technology, or giving our shareholders an exit. Once you’re public, now you have a lot of options.

The IPO was a seminal moment for the company, and I think that the story is a great public market story. The technology is very complex, but it can be boiled down to be understood by a layperson. Cell therapy is definitely the place to be, and we would argue that GDT is the hottest space in cell therapy.

DA: As a closing thought, can you discuss how you see the cell therapy landscape in general changing over the next several years and what impact you think GDT cells and TC Biopharma more specifically will have?

BK: Obviously, we are believers in the cell therapy movement. I think that the real next iteration for cell therapy is combination therapies within the cell therapy world. The immune system is the result of literally millennia of development. The next iteration for cell therapies is leveraging that system to specifically fight off disease states. This will present a great option for very difficult-to-treat indications, as well as things like aging. It’s an exciting place to be. Taking unmodified and modified cells and putting them together into a system to recreate the immune response in its totality on an exogamous basis sounds like magic, but it is within reach.

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